In 1884, Karl Koller, Australian ophthalmologist, introduced the use of substances with anesthetic activity in medicine field. From that initial study, the search for natural or synthetic compounds with the property to promote the blocking of neural stimulus transmission has been investigated by a plurality of research groups. In 1935, Southworth and Dabbs, in Xylocaine: a superior agent for conduction anesthesia. Curr Res Anesth Analg, 32, 159-170, synthesized alkaloid isomers with anesthetic properties. Subsequently, Löfgren and Takman, in 1952, in the article Studies on Local Anaesthetics VII. Acta Chemica Scadinavica, 6, 1010-1015, synthesized a compound that was named lidocaine from that on, such compound has a remarkable local anesthetic activity, whose formula is represented by the formula I:

Lidocaine, 1-(2-(dyethylamine)N-dymethylfenyl)-acetamide, commercially registered under the name Xylocaine®, besides its well-known local anesthetic activity, applied on blocking the process of depolarization of the excitatory membranes, in a mechanism associated with the inhibition of the sodium channels, has useful clinical properties to the control of cardiac arrhytmia, promoting a reduction in the cardiac contractibility and hypotension, reduction and/or inhibition of tumour growth, bactericidal ability and modification of plasma cells, making interferece in virus absorption possible and, thus, providing antiviral effect, according to as described in EP 0643964.
Recent studies, carried out by Hollmann and Durieux, in Local anesthetics and the inflammatory response: a new therapeutic indication? Anesthesiology. 2000, 93, 858-875, point out to evidences that local anesthetic agents, including lidocaine, also hold the property of preventing from inflammatory processes. In these cases, however, the modus operandi and, most of all, the potential clinical applicability of these properties remain little explored.
It was verified that bronchoalveolar lavage of patients suffering from asthma often inhibited eosinophils survival stimulated by different cytosines, including the IL-5, as taught by Hunt et al., in Effect of Nebulized Lidocaine on Severe Glucocorticoid-Dependent Asthma. Mayo Clin. Proc., 1996, 71, 361-368. Thus, it was confirmed that, in fact; when lidocaine was used in a procedure to collect the bronchoalveolar effluent it was itself responsible for the significant survival block of eosinophils observed in vitro.
Asthma is a complex and heterogeneous inflammatory lung disease that appears strongly associated with a hyperresponsivity to bronchitis, eosinophil infiltrate and recurring episodes of getting short of air, whistling noise in the chest and coughing. Such signs and symptoms are related to the obstruction of the airways that may be spontaneously reversible or after treatment. It is known that a inflammation of the respiratory passages plays an important role in the pathogenesis of the disease. The process is remarkable by the increase in the production of IgE and a polarization of the response Th2 with increasing levels of cytocines type 2, including IL-4, IL-5 and IL-13, besides beta chemokines. An important aspect of asthma pathogenesis is the accumulation of a plurality of eosinophils in the respiratory passages, a phenomenon that occurs in strict correlation with the seriousness of the disease. Since long ago eosinophils have been associated to allergic diseases and there are increasing evidences that they play a pro-inflammatory role.
There are substantial evidences in literature that mediators derived from eosinophils, including basic cationic proteins, cytocines and inflammatory lipidic mediators, would be associated with one another in a direct and causal relation to the symptoms and pathological signs observed in the asthmatic set.
The therapeutical arsenal therapeutic available for the treatment of asthma is relatively ample, but, in general, the medical practice is restricted basically to the use of two classes of medicines; the steroidal anti-inflammatory agents and the bronchodilators type beta 2 adrenergic, both of them are recognized bring benefits, which are limited by a plurality of side effects.
The bronchodilator agents link to the receptors type beta 2 adrenergic located on the surface of the non-striated muscle cells that line the bronchial tubes. This connection activates a complex signaling cascade that results in the reduction of the intracellular levels of calcium and subsequent relaxation of the non-striated muscle, clearing upper respiratory passages and protecting against muscle spasm. However, recent studies point out to a life risk increase in patients that make chronical use of bronchodilators unaccompanied by glucocorticoids. The isolated use of the bronchodilator is of elevated risk, because while it transmits to the patient a relieving sensation of symptoms, it masks the progressive inflammatory picture deterioration.
Epidemiological studies have shown that treatment of asthma with bronchodilators do not prevent the increasing morbidity and mortality. Children with persistent asthma symptoms until adulthood show reduced lung function. Adult patients that suffer from asthmatic bronchitis present na accelerated decline in lung volume. Therefore, there is a tendency to focus the asthma therapy on the inflammatory processes.
In this sense, therapy with glucocorticoids agents is the most effective nowadays in order to control serious asthma because it reduces the allergic response started off by eosinophils and by its anti-inflammatory effects as a result of the modulation of the genic transcription. The connection of these agents to specific receptors present in the cytoplasm of target cells is followed by the translocation of steroidal-receptor complex to the nucleus, dimerization and coupling of the dimer to the so-called “responsive elements of glucocorticoids” in the nuclear DNA, this way activating or restraining the transcription mechanisms. The suppressive effect of the glucocorticoids agents on the transcription of an expressive number of genes of inflammatory mediators, including cytocines (IL-4, IL-5, IL-13, GM-CSF, etc) e chemokines (eotaxin, MCP-1, etc), is well established. Although glucocorticoid agents therapy, in general, is successful to control the symptoms of asthma, the severe systemic effects of these medicaments and the refractory to the treatment presented by a subgroup of asthmatic individuals, point out to a unequivocal necessity of new alternative therapies.
In the literature, there are clear indications that long-term treatment with nebulized lidocaine resulted in relief of asthma symptoms, diminishing the dependency to the treatment with steroidal anti-inflammatory in 20 out of 24 patients investigated (Hunt, L. W., Swedlund, H. A., Gleich, G. J. Effect of Nebulized Lidocaine on Severe Glucocorticoid-dependent Asthma. Mayo Clin. Proc., 1996, 71, 361-368).
According to literature, the anti-asthma effect of lidocaine would be associated with its capacity to bring eosinophils to death by apoptosis, eliminating, this way, crucial effector cells for the pathogenesis of asthma.
Besides the acknowledged anti-inflammatory activity, lidocaine presents other actions that, at least in thesis, could contribute to an anti-asthma action. As for example, it affects the respiratory function acting directly on the respiratory passages muscles, modulating intracellular levels of calcium in non-striated muscle fibers. It is well-know that the anti-inflammatory activity of lidocaine is not restricted to the action on the eosinophils. Some studies report its inhibitory action over neutrophyl and monocytes actions, including the synthesis of phosphatidylcholine, tirosine phosphorylation, releasing of superoxide, releasing of lysosome enzymes, phagocytosis, aggregation, adherence to the membrane of endothelial cells and expression/releasing of molecules of cellular adhesion. However, the actions of lidocaine and other local anesthetics on the respiratory passages are heterogeneous and complex. There are strong evidences that lidocaine prevents risky bronchospasm in response to different stimuli induce bronchoconstriction, including instrumentation of respiratory passages, hyperosmolar saline solution, asthma induced by exercise and histamine. It is important to notice that the attenuation of bronchospasm by histamine, observed in patients treated with lidocaine, occurs independently of the anesthetic action, since the local anesthetic dyclonine was ineffective.
In healthy individuals, lidocaine aerosol produces few effects in the pulmonary mechanics. However, individuals with elevated reactivity in the respiratory passages, including asthmatic ones, lidocaine administered through aerosol may induce a remarkable initial bronchoconstrictor effect. At least two hypotheses have been raised to explain this effect apparently paradoxical. First of all, local anesthesia of the respiratory passages could prevent from an appropriate sensorial perception of inspiration and expiration function regulatory mechanisms. Actually, a state of inspiratory incoordination has been reported after anesthesia by lidocaine during the procedures of laryngoscopy with subsequent obstruction of the upper respiratory passages. Secondly, lidocaine could favor the bronchoconstrictive response inhibiting bronchodilators neurogenic reflexes, mediated by sympathetic innervation and others.
On the other hand, the use of lidocaine in the treatments of asthma presents the disadvantage of the anesthetic activity characteristic of this molecule.
It is therefore evident that there are inconvenient effects when using lidocaine in the treatment of asthma, since it causes discomfort to the patients.
As a consequence, there is the necessity to provide alternatives in order to overcome the inconvenients previously pointed out.
In this way, it constitutes one of the main characteristics of the present invention: the development of compounds with anti-inflammatory and spasmodic effectiveness similar or superior to the one made evident by lidocaine, but with local anesthesia minimized.